The estrogen receptor is a critical driver in breast cancer (Di Cosimo, S. & Baselga, J. (2010) Nat. Rev. Clin. Oncol). Since about 60-70% of breast cancer (BC) is estrogen receptor positive (ER+), modulation of estrogen activity and/or synthesis is the main therapeutic strategy in the treatment of ER+BC. Effective hormonal therapies are used across many lines of therapy to decrease estrogen/ligand (ovarian suppression, aromatase inhibitors). Selective Estrogen Receptor Modulators (SERMs) bind to ER, downregulate ER levels and antagonize ER transcriptional activity. Selective Estrogen Receptor Degraders (SERDs) bind to ER and degrade ER. Many breast cancer patients relapse or develop resistance in their tumors, which are often still dependent on the ER.
The N-methyl-D-glucamine salt of (E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid (GDC-0810, ARN-810, Seragon Pharmaceuticals, Inc., Genentech Inc., CAS Registry Number 1365888-06-7) is an oral, non-steroidal, estrogen receptor alpha (ERα) antagonist and selective estrogen receptor degrader (SERD) that competes with estrogens for binding to the estrogen receptor with low nanomolar potency (U.S. Pat. No. 8,299,112; U.S. Pat. No. 8,455,534; Lai et al (2015) J. Med. Chem. 58:4888-4904). A Phase I study evaluated the oral selective estrogen receptor degrader GDC-0810 (ARN-810) in postmenopausal women with estrogen receptor positive (ER+) HER2−, advanced/metastatic breast cancer (Zhou et al, “Selective Estrogen Receptor Degrader (SERD) activity in ESR1 mutant models”, AACR Poster #1864; Joseph et al, “Discovery of GDC-0810 a novel, non-steroidal selective estrogen receptor degrader with robust activity in pre-clinical models of endocrine-resistant breast cancer”, AACR Poster #5053; Dickler M N, et al (2015) AACR Annual Meeting, Clinical Trials of New Drugs in Breast Cancer, Apr. 20, 2015, Abstract CT231). GDC-0810 has demonstrated tumor regression in tamoxifen sensitive and resistant BC models.
In contrast to first generation ER antagonists, such as tamoxifen, GDC-0810 fully antagonizes the response of ER to estrogens and induces proteosomal degradation of ER-α in breast cancer cell lines. These bipartite activities result in full antagonism of ER-target gene transcription in breast cancer cell lines in vitro. The result is robust inhibition of ER signaling, and in turn, inhibition of breast tumor cell proliferation. Unlike fulvestrant, which is also an ER antagonist and degrader, GDC-0810 has a nonsteroidal chemical backbone and displays oral bioavailability.